The CaV3.3 calcium channel is the major sleep spindle pacemaker in thalamus

Low-threshold (T-type) Ca2+ channels encoded by the CaV3 genes endow neurons with oscillatory properties that underlie slow waves characteristic of the non-rapid eye movement (NREM) sleep EEG. Three CaV3 channel subtypes are expressed in the thalamocortical (TC) system, but their respective roles for the sleep EEG are unclear. CaV3.3 protein is expressed abundantly in the nucleus reticularis thalami (nRt), an essential oscillatory burst generator. We report the characterization of a transgenic CaV3.3−/− mouse line and demonstrate that CaV3.3 channels are indispensable for nRt function and for sleep spindles, a hallmark of natural sleep. The absence of CaV3.3 channels prevented oscillatory bursting in the low-frequency (4–10 Hz) range in nRt cells but spared tonic discharge. In contrast, adjacent TC neurons expressing CaV3.1 channels retained low-threshold bursts. Nevertheless, the generation of synchronized thalamic network oscillations underlying sleep-spindle waves was weakened markedly because of the reduced inhibition of TC neurons via nRt cells. T currents in CaV3.3−/− mice were <30% compared with those in WT mice, and the remaining current, carried by CaV3.2 channels, generated dendritic [Ca2+]i signals insufficient to provoke oscillatory bursting that arises from interplay with Ca2+-dependent small conductance-type 2 K+ channels. Finally, naturally sleeping CaV3.3−/− mice showed a selective reduction in the power density of the σ frequency band (10–12 Hz) at transitions from NREM to REM sleep, with other EEG waves remaining unaltered. Together, these data identify a central role for CaV3.3 channels in the rhythmogenic properties of the sleep-spindle generator and provide a molecular target to elucidate the roles of sleep spindles for brain function and development.